Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1993-08-11
1994-09-13
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 59, 560126, 560147, 560152, 560170, 564162, 564165, 564191, 564193, 564201, 564203, 568862, 568863, C07C 6976
Patent
active
053470397
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the selective preparation of syn derivatives of 3,5-dihydroxypentanoic acid of general formula: ##STR1## by diastereoselective reduction of a chiral or racemic hydroxyketone of general formula: ##STR2##
In the formulae (I) and (II), carbon atoms, an alkylthio radical in which the alkyl part contains 1 to about 4 carbon atoms, an amino radical, an alkylamino radical in which the alkyl part contains 1 to about 4 carbon atoms or a dialkylamino radical in which each alkyl part contains 1 to about 4 carbon atoms, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH-- or --C.tbd.C-- radical and R.sub.1 represents an optionally substituted aliphatic, alicyclic, aromatic or heteroaromatic radical or a radical ##STR3## in which R.sub.2 represents a halogen atom or an alkoxy radical in which the alkyl part contains 1 to about 4 carbon atoms, an alkylthio radical in which the alkyl part contains 1 to about 4 carbon atoms, an arylthio radical, an amino radical, a monoalkylamino radical in which the alkyl part contains 1 to about 4 carbon atoms or a dialkylamino radical in which each alkyl part contains 1 to about 4 carbon atoms and R.sub.3 represents a hydrogen atom or is identical to R.sub.2.
More particularly, R represents a radical R.sub.1 --Y-- in which Y represents a --CH.sub.2 CH.sub.2 -- or --CH.dbd.CH-- radical and R.sub.1 represents an alicyclic, aromatic or heteroaromatic radical which corresponds to that of the products of general formula (I) in which Z represents an alkoxy radical or a hydroxyl radical and corresponding lactones which inhibit the synthesis of cholesterol by inhibition of the enzyme HMG-CoA reductase and which are more particularly described in American U.S. Pat. Nos. 4,375,475, 4,474,971, 4,613,610 and 4,863,957, in International Applications PCT WO 84/02903, WO 84/02131, WO 86/07054, WO 86/03488, WO 86/00307 and WO 86/00598 and in European Patent Applications EP-A-0,303,446 and EP-A-0,326,386.
Very particularly advantageous are the products of general formula (I) for which R represents a radical R.sub.1 --Y-- in which Y represents --CH.dbd.CH-- and R.sub.1 represents the [2-(4-fluorophenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]- or [2-(4-fluoro -3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]-radic al or the [4-( 4-fluorophenyl)-2-isopropyl- 1 -oxo- 1,2-dihydro-3-isoquinolyl]- radical.
The reduction of .beta.-hydroxyketones using boranes or borinates in combination with sodium borohydride is known [K. Narasaka et F. C. Pai, Tetrahedron, 40, 2233 (1984); K. Prasad et al., Tetrahedron Letters, 28, 155 (1987); K. Prasad et al., Chem. Letters, 1923 (1987); T.R. Verhoeven et al., Tetrahedron Letters, 26, 2951 (1985); W. Bartmann et al., J. Med. Chem., 33, 61 (1990); D. R. Sliskovic et al., J. Med. Chem., 33, 31 (1990); N. Balasubramanian et al., J. Med. Chem., 32, 2041 (1989); G.E. Stokker et al., J. Med. Chem., 28, 347 (1985)]. The stereoselective reduction of .delta.-hydroxy-.beta.-ketoesters using zinc borohydride is also known [K. Prasad et al., Helv. Chim. Acta, 69, 803 (1986)].
The known processes require the use of low temperatures to give good selectivity towards "syn" isomers.
It has now been found, and it is this which forms the subject of the present invention, that the products of general formula (I) may be obtained, from the products of general formula (11), practically pure and free from the "anti" isomer of general formula: ##STR4## in which R and R.sub.1 are defined as above, by using as reducing agent a sodium or potassium borohydride or cyanoborohydride in combination with a titanium derivative.
The titanium derivatives which are particularly well suited are the derivatives of formula Ti(R.sub.4).sub.4 in which the symbols R.sub.4, which are identical or different, represent a halogen (chlorine) atom or a radical OR' or OCOR' in which R' represents an alkyl radical containing 1 to about 4 carbon atoms.
The titanium derivatives may optionally be prepared in situ by introducing into the reaction mixture the reactants necessary for their for
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Bonini, C. et al. Gazz. Chim. Ital 121 (2) 75-80 1991.
Leon Patrick
Massonneau Viviane
Radisson Xavier
Killos Paul J.
Parker III Raymond S.
Rhone-Poulenc Rorer S.A.
Savitzky Martin F.
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